SEMINAR

Seminar

Hepatorenal syndrome

Pere Ginès, Mónica Guevara, Vicente Arroyo, Juan Rodés

Hepatorenal syndrome (HRS) is a common complication of advanced cirrhosis, characterised by renal failure and major
disturbances in circulatory function. Renal failure is caused by intense vasoconstriction of the renal circulation. The
syndrome is probably the final consequence of extreme underfilling of the arterial circulation secondary to arterial
vasodilatation in the splanchnic vascular bed. As well as the renal circulation, most extrasplanchnic vascular beds are
vasoconstricted. The diagnosis of HRS is currently based on the exclusion of other causes of renal failure. The
prognosis is very poor, particularly when there is rapidly progressive renal failure (type 1). Liver transplantation is the
best option in patients without contraindications to the procedure, but it is not always possible owing to the short
survival expectancy. Therapies introduced during the past few years, such as vasoconstrictor drugs (vasopressin
analogues, ␣-adrenergic agonists) or the transjugular intrahepatic portosystemic shunt, are effective in improving
renal function. Nevertheless, liver transplantation should still be done in suitable patients even after improvement
of renal function because the outcome of HRS is poor. Finally, recent findings suggest that the risk of developing HRS
in the setting of spontaneous bacterial peritonitis may be reduced by the administration of albumin together with
antibiotic therapy, and that of HRS occurring in severe alcoholic hepatitis can be lowered by administration of
pentoxifylline. Although these findings need to be confirmed, these two strategies represent innovative approaches to
lower the frequency of HRS in clinical practice.

Renal failure is a common complication of patients with
advanced cirrhosis.1,2 It generally indicates a poor
prognosis because of the combined detrimental effect of
renal and liver failure. In some cases, renal failure in
cirrhosis is due to aetiological factors that also lead to
renal failure in patients without liver disease, such as
severe dehydration, shock (haemorrhagic or septic), or
nephrotoxic drugs, or is the consequence of an intrinsic
renal parenchymal disease, such as glomerulonephritis.
However, in other cases renal failure in cirrhosis occurs in
the absence of these factors and with normal renal
histology. This disorder is known as hepatorenal
syndrome (HRS). It is caused by intense vasoconstriction
of the renal circulation, which leads to a pronounced
reduction in glomerular filtration rate (GFR).1–5 Although
HRS was described more than 50 years ago, many
features of its pathogenesis and natural history remained
unknown for many years. No effective treatment existed
until very recently. The aim of this seminar is to provide
an up to date revision of HRS, with special emphasis on
its diagnosis and management.
Definition
HRS generally occurs in patients with advanced liver
disease and portal hypertension. It is characterised by a
combination of disturbances in circulatory and kidney
function.6 The principal abnormality in the systemic
circulation is low arterial pressure due to greatly reduced
total systemic vascular resistance. Kidney function is
much impaired because of severe reduction of renal blood
flow. The reduction in renal blood flow is pathogenetically
Lancet 2003; 362: 1819–27
Liver Unit, Hospital Clínic, Institut d’Investigacions Biomèdiques
August Pi-Sunyer, University of Barcelona School of Medicine,
Barcelona, Catalunya, Spain (P Ginès MD, M Guevara MD, V Arroyo MD,
J Rodés MD)
Correspondence to: Dr Pere Ginès, Liver Unit, Hospital Clínic,
Villarroel 170, 08036 Barcelona, Catalunya, Spain
(e-mail: gines@medicina.ub.es)
related to the impairment in the systemic circulatory
function. HRS occurs predominantly in the setting of
cirrhosis, but it can also develop in other types of severe
chronic liver disease, such as alcoholic hepatitis, or in
acute liver failure.7–9
Pathogenesis
The pathophysiological hallmark of HRS is
vasoconstriction of the renal circulation.1–4,6,10–13 The
mechanism of the vasoconstriction is incompletely
understood; it may be multifactorial, involving
disturbances in the circulatory function and activity of
systemic and renal vasoactive mechanisms. There is
severe arterial underfilling in the systemic circulation due
to pronounced arterial vasodilatation in the splanchnic
circulation, which is related to the presence of portal
hypertension. In the kidney, by contrast, there is striking
vasoconstriction. A detailed analysis of these mechanisms
and their possible role in the pathogenesis of HRS is
beyond the scope of this paper and can be found
elsewhere.14,15
The theory that best fits with the observed changes in
renal and circulatory function in HRS is the arterial
vasodilatation theory, which proposes that HRS is the
result of the action of vasoconstrictor systems (ie, the
renin-angiotensin system, the sympathetic nervous
system, and arginine vasopressin) on the renal circulation
activated as a homoeostatic response to improve the
extreme underfilling of the arterial circulation
Search strategy and selection criteria
A systematic review of all articles published in English was
done with the help of PubMed Services with the keywords
“cirrhosis”, “liver failure”, “renal failure”, and “hepatorenal
syndrome” for the period 1960–2002. Priority was given to
prospective clinical studies published in journals with high
impact factors. For topics on which there was not enough
published information to provide evidence-based criteria, we
used our own clinical judgment and experience to fill the
gaps.

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SEMINAR

Incidence
Therapeutic interventions Pathogenesis
HRS is thought to be a common complication of patients
with advanced cirrhosis. However, most of the classic
studies on the incidence of HRS in patients with cirrhosis
Liver transplantation Cirrhosis were done many years ago and used non-standard
Increased intrahepatic diagnostic criteria.1,24–27 Therefore, neither the current
vascular resistance incidence of HRS nor its frequency relative to other
causes of renal failure in cirrhosis is known. In the largest
study published so far, the probability of HRS in patients
Transjugular intrahepatic Portal hypertension with cirrhosis and ascites was 40% over 5 years.27
portosystemic shunts
Increased splanchnic
production of Clinical and laboratory findings
vasodilators In the setting of cirrhosis, HRS generally occurs in late
stages of the disease when patients have already had
several episodes of some of the major complications of
Splanchnic cirrhosis, especially ascites. Patients with ascites showing
Vasoconstrictors
vasodilatation renal sodium retention together with dilutional
hyponatraemia are at high risk of developing HRS.27
The dominant finding of HRS is renal failure, although
Severe arterial underfilling many patients have other manifestations such as
electrolyte disorders, cardiovascular and infectious
Low arterial complications, and complications related to liver disease.
pressure In the past, HRS was generally diagnosed when
oligoanuria developed.1,24–26 Currently, however, with the
Stimulation of widespread use of frequent biochemical monitoring, HRS
vasoconstrictor is most frequently first diagnosed by a finding of
systems increasing concentrations of serum creatinine or blood
Vasoconstriction urea nitrogen. In some patients, there is a rapid rise in
of limbs and serum concentrations of both creatinine and blood urea
cerebral nitrogen to very high values.3,26 Most of these patients
circulation show progressive oligoanuria. In other patients, the
increases in serum creatinine and blood urea nitrogen are
Renal vasoconstriction moderate, with no (or very little) tendency to progress
Renal vasoconstrictors over time, at least in the short term.28,29 These two
>renal vasodilators different patterns of progression of renal failure define two
different clinical types of HRS.6 The rate of progression
Renal replacement Hepatorenal used to define HRS type 1 has been arbitrarily set as a
therapy syndrome 100% increase in serum creatinine reaching a value
greater than 221 ␮mol/L (2·5 mg/dL) in less than
Figure 1: Proposed pathogenesis of HRS in cirrhosis, according 2 weeks.6 Patients who do not meet these criteria of
to the arterial vasodilatation theory, and effective therapeutic progression are deemed to have type 2 HRS. Some
interventions patients with type 2 eventually develop a sudden
progression of renal failure after weeks or months of stable
(figure 1).6,15–17 As a result of this increased activity of the serum creatinine concentrations and may then meet the
vasoconstrictor systems, renal perfusion and GFR are criteria for type 1. In patients with type 1 HRS, GFR is
greatly reduced but tubular function is preserved. These very low, commonly below 20 mL/min, and serum
features differ from those of acute tubular necrosis, in creatinine concentrations are very high (average around
which renal failure is associated with seriously impaired 356 ␮mol/L). By contrast, most patients with type 2 HRS
tubular function. The vasoconstrictor systems also lead have less severely abnormal GFR and creatinine
to the retention of sodium (renin-angiotensin and concentrations (average 178 ␮mol/L). The predominant
sympathetic nervous system) and free water (arginine clinical feature of patients with type 1 HRS is severe renal
vasopressin) that occurs in advanced cirrhosis.2,16,17 Most failure, and that of patients with type 2 HRS is recurrent
available data suggest that the arterial underfilling is due ascites because there is little or no response to diuretics
to vasodilatation of the splanchnic circulation related to owing to the combination of low GFR and pronounced
increased splanchnic production of vasodilator activation of antinatriuretic systems.6 An important
substances, particularly nitric oxide.18,19 In the early phases clinical difference between the two types of HRS is that
of decompensated cirrhosis, renal perfusion is maintained patients with type 1 have a very poor short-term outcome
within the normal range because of increased synthesis of compared with that of patients with type 2.
renal vasodilator factors (mainly prostaglandins). In later Besides renal failure, patients with HRS have sodium
phases of the disorder, renal perfusion cannot be retention with features of salt and water overload. In
maintained because the extreme arterial underfilling most, sodium retention is already present and pronounced
causes maximum activation of vasoconstrictor systems, before the development of HRS, but renal sodium
decreased production of renal vasodilator factors, or both, excretion can be impaired further when renal failure
and HRS develops. The activation of vasoconstrictor develops owing to the reduction in GFR and greater
systems also results in vasoconstriction of some vascular activation of antinatriuretic systems. The consequently
beds other than the kidneys, including the arms, legs, and increased positive sodium balance results in weight gain
brain.20–23 The splanchnic area escapes the effect of due to an increase in ascites volume and peripheral
vasconstrictors probably because of the greatly increased oedema. Hyponatraemia is almost universal in HRS, so if
local production of vasodilators. the serum sodium concentration in a patient with cirrhosis

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and renal failure is normal, the diagnosis of HRS is very
unlikely and the patient should be investigated for a
different cause of renal failure. Hyponatraemia is due to
impaired renal capacity to excrete solute-free water, which
results in disproportionate retention of water relative to
the amount of sodium retained (dilutional
hyponatraemia).30 This disorder is pathogenetically
related to increased arginine vasopressin release in
response to severe arterial underfilling and exists in most
cases before the development of HRS, but it worsens as
renal failure progresses.16,17,30 Hyperkalaemia is also
common but moderate in most cases. High rates of
increase in plasma potassium concentrations are
infrequent. Nevertheless, potassium concentrations
should be monitored frequently and hyperkalaemia
treated aggresively, if present, to avoid cardiac
complications. Severe metabolic acidosis is also
uncommon in HRS except for patients who develop a
severe infection.
Cardiovascular function is severely affected in patients
with HRS. The total systemic vascular resistance is much
reduced, and arterial pressure low in most cases despite
pronounced activation of major vasoconstrictor
mechanisms, such as the renin-angiotensin and
sympathetic nervous systems.2,6,17,20,21,31,32 Cardiac output is
increased in most patients but may be reduced in
some,15,20,21,33 whereas arterial pressure is low but stable
(average mean arterial pressure around 70 mm Hg).
When there is haemodynamic instability, an infectious
complication should be suspected. Except for arterial
pressure, the other cardiovascular abnormalities
mentioned are not recognised in the clinical setting unless
invasive vascular monitoring is done and vasoconstrictor
factors are measured. However, these procedures are
generally not required in the clinical management of
patients with HRS. Pulmonary oedema, which is a
common and severe complication of acute renal failure in
the absence of liver disease, is very rare in patients with
HRS unless they are treated aggressively with plasma
expanders.
Severe bacterial infections, especially septicaemia
(either spontaneous or related to indwelling catheters),
spontaneous bacterial peritonitis, and pneumonia, are
common complications in patients with HRS and are
major causes of death.27,34,35 Both the renal failure and
advanced liver disease probably account for increased
susceptibility to the infections.
Finally, most patients with HRS show signs and
symptoms of advanced liver failure and portal
hypertension, particularly jaundice, coagulopathy,
malnutrition, and hepatic encephalopathy, although HRS
develops in a few patients with only moderate liver
insufficiency.32,34,35 The presence of ascites is universal in
patients with HRS, so the lack of ascites in a patient with
cirrhosis and renal failure argues against HRS as the cause
of renal failure and points towards other causes,
particularly prerenal failure due to volume depletion
because of excessive diuresis.
Precipitating factors
In some patients, HRS develops spontaneously without
any apparent triggering event, whereas in others it occurs
in close chronological relation to some precipitating
factors that can cause circulatory dysfunction and
subsequent renal hypoperfusion.1,3,15,24,36 Well-known
precipitating factors include bacterial infections, large-
volume paracentesis without plasma expansion, and
gastrointestinal bleeding. Among the different types of
bacterial infections that occur in cirrhosis, a clear
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SEMINAR
chronological and pathogenetic relation between the
infection and HRS has been established only for
spontaneous bacterial peritonitis.37,38 This disorder is
characterised by the spontaneous infection of ascites, in
most cases by gram-negative bacteria of enteric origin, in
the absence of infection of intra-abdominal organs or gut
perforation.39 About 20% of patients with spontaneous
bacterial peritonitis develop HRS during or immediately
after the infection—type 1 in most cases.37,38 Whether
HRS can also occur as a consequence of other severe
bacterial infections has not been studied. Another well-
known precipitating factor of HRS is large-volume
paracentesis without plasma expansion.40 Up to 15% of
patients with ascites develop HRS when large volumes of
ascitic fluid (more than 5 L) are removed without the
administration of a plasma expander. This association is
one of the reasons why intravenous albumin should be
administered when large-volume paracentesis is done.41
Finally, renal failure occurs in about 10% of patients with
cirrhosis and gastrointestinal bleeding.42,43 However, a
substantial proportion of episodes of renal failure after
gastrointestinal bleeding are due to acute tubular necrosis
related to hypovolaemic shock and not to HRS.43
Intravascular volume depletion (ie, diuretic-induced,
extrarenal fluid losses) has classically been considered as a
triggering factor for HRS.1 However, no convincing
evidence has yet been reported to support this
pathogenetic relation.
Prognosis
Of all the complications of cirrhosis, HRS has the worst
prognosis. The survival expectancy is very low1,2,6,27 and
spontaneous recovery very rare. The main determinant of
survival is the type of HRS. In type 1, hospital survival is
less than 10% and the expected median survival time only
2 weeks.26,27 By contrast, patients with type 2 have a much
longer median survival time (about 6 months; figure 2).
The second determinant of survival is the severity of liver
disease.34,35 Patients with severe liver failure (Child-Pugh
class C) have a much worse outcome than those with
moderate liver failure (class B). For many years, the
development of renal failure was judged not to contribute
to the dismal outcome of the HRS, and death was thought
to be due mainly to the liver disease. However, recent
studies suggest that renal failure is an important
determinant of the outcome, since patients in whom renal
1·0
0·8
Survival probability
Type 2
0·6
0·4
p=0·001
0·2 Type 1
0
0 2 4 6 8 10 12
Time (months)
Figure 2: Survival of patients with cirrhosis after the diagnosis
of type 1 or type 2 HRS
PG, unpublished observations.
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function improves after therapy survive longer than those
without such improvement.34,35
Diagnostic approach
The initial step in the diagnosis of HRS is to demonstrate
the existence of renal failure (ie, low GFR). The serum
creatinine concentration is generally deemed a better
marker of GFR than the blood urea nitrogen
concentration, because the latter can vary in the absence
of changes of GFR (eg, gastrointestinal bleeding, diets
high or low in protein). However, serum creatinine
concentration is not an ideal marker of GFR in cirrhosis
because it is generally lower than expected for any given
GFR owing to low endogenous production of creatinine
related to the reduced muscle mass that occurs in most
patients with advanced cirrhosis.44,45 Nevertheless, since
the use of more sensitive clearance techniques to measure
GFR is expensive and not available in all settings, serum
creatinine concentration is currently the method of choice
to estimate GFR in cirrhosis.6 In patients with cirrhosis,
steady-state GFR of 100 mL/min, 50 mL/min,
25 mL/min, 12 mL/min, and 6 mL/min are associated
with serum creatinine concentrations of about 71 ␮mol/L,
88 ␮mol/L, 160 ␮mol/L, 195 ␮mol/L, and 354 ␮mol/L,
respectively (MG, unpublished observations). There is
consensus to establish the diagnosis of HRS when serum
creatinine has risen above 133 ␮mol/L.6 In patients with
high serum creatinine concentrations who are receiving
diuretics, serum creatinine should be remeasured after
diuretic withdrawal, since the use of diuretics can be
associated with a slight and reversible increase in serum
creatinine concentrations.
Because of the lack of specific diagnostic tests, the
diagnosis of HRS must always be made after exclusion of
other disorders that can cause renal failure in cirrhosis.6
An algorithm for the diagnosis of HRS is shown in
figure 3. Acute renal failure of prerenal origin due to
gastrointestinal fluid losses (vomiting, diarrhoea,
nasogastric tube) or renal fluid losses (overdiuresis due to
excessive diuretic treatment) should be investigated by
Renal failure
(serum creatinine >133 ␮mol/L)
Fluid losses
Prerenal failure
Shock
Acute tubular necrosis
Signs of infection
Infection-induced
renal failure
Persistence of
renal failure after
resolution of infection
Hepatorenal syndrome
Figure 3: Diagnostic flow chart of HRS in patients with cirrhosis
In some cases, renal failure may not be due to a single cause but to a combination. In these cases, the identification of the causative factors may be
difficult with the current diagnostic tools.
1822
For personal use. Only reproduce with permission from The Lancet publishing Group.
history and physical examination in all patients with renal
failure. If renal failure is secondary to volume depletion,
renal function improves rapidly after volume expansion,
whereas no improvement occurs in patients with HRS.
Even if there is no history of fluid losses, renal function
should be assessed after diuretic withdrawal and volume
replacement to rule out any subtle reduction in plasma
volume as the cause of renal failure. Although there is no
absolute agreement as to the type and amount of plasma
expander to be used for this purpose, there is international
consensus on the use of 1500 mL isotonic saline.6 The
presence of shock before the onset of renal failure
precludes the diagnosis of HRS and points towards a
diagnosis of acute tubular necrosis.43 Hypovolaemic shock
due to gastrointestinal bleeding is common in cirrhosis
and is easily recognised. However, septic shock may be
more difficult to diagnose because of the lack of
symptoms of bacterial infection in some patients with
cirrhosis and the fact that arterial hypotension due to
sepsis can be erroneously attributed, at least in the early
stages, to the advanced liver disease.46 Therefore, a
bacterial infection should always be ruled out (leucocyte
count, examination of ascitic fluid, cultures, C-reactive
protein) before the diagnosis of HRS is made. Conversely,
some patients with cirrhosis and bacterial infections
develop transient renal failure, which resolves in most
after resolution of the infection.37 Therefore, HRS should
be diagnosed only if renal failure persists after complete
resolution of the infection. Patients with cirrhosis are at
high risk of developing renal failure during treatment
with non-steroidal anti-inflammatory drugs or
aminoglycosides.47–49 Therefore, treatment with these
drugs in the days or weeks preceding the development of
renal failure should always be ruled out. Renal failure can
also occur after the administration of radiocontrast
agents.50 However, whether patients with cirrhosis are at
high risk for the development of this complication has
never been assessed. Finally, patients with cirrhosis can
also develop renal failure due to parenchymal renal
diseases, particularly glomerulonephritis.51,52 This may
Nephrotoxic drugs
History and physical examination
Nephrotoxic
renal failure
Proteinuria and/or
haematuria
Blood and urine chemistries
Parenchymal
renal disease
Abnormal renal
ultrasonography Renal ultrasonography
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occur in all causes of cirrhosis but is particularly common
in the setting of chronic hepatitis B or C infection or
chronic alcoholism. These cases can be recognised by the
presence of proteinuria, haematuria, or both. The
diagnosis can be confirmed by renal biopsy in selected
cases.
The differential diagnosis between HRS and acute
tubular necrosis is especially difficult. Early studies
emphasised the importance of urinary indices, especially
urine sodium concentration, in the differential
diagnosis.1,24 Urine sodium concentration is very low
(<10 mmol/L) in most patients with HRS as a result of
the preserved tubular function and concomitant activation
of sodium-retaining systems. In acute tubular necrosis, by
contrast, urine sodium concentration is not low
(>10 mmol/L); the altered tubular function impairs the
reabsorption of sodium. However, urine sodium
concentration can be very low in patients with cirrhosis
and acute tubular necrosis and may not be very low in
some patients with HRS.6,53 Therefore, an international
consensus was reached that this variable should not be
used as a major criterion to differentiate between HRS
and acute tubular necrosis in cirrhosis.6 Because of the
lack of objective measures, acute tubular necrosis in
cirrhosis should be suspected when renal failure develops
in the setting of hypovolaemic or septic shock or
administration of nephrotoxic agents. Therefore, the
presence of these conditions immediately before the
development of renal failure is currently deemed sufficient
to exclude HRS and make the diagnosis of acute tubular
necrosis.6 Nevertheless, there is a clear need for objective
indices to differentiate between HRS and acute tubular
necrosis in cirrhosis. In this regard, the possible use of
other renal indices, such as the fractional excretion of
urea, should be explored.54
There is no published information on the comparative
frequency of the different causes of renal failure in
patients with cirrhosis. In a current prospective study of
renal failure in patients with cirrhosis being carried out at
our unit, which so far includes 142 episodes of renal
failure diagnosed over 1 year, the frequency of the
different causes of renal failure is: 32% infection-induced
renal failure; 24% parenchymal renal diseases; 22%
prerenal failure; 11% acute tubular necrosis; 8% HRS;
and 3% nephrotoxic renal failure (PG, unpublished).
Management of type 1 HRS
Patients with suspected type 1 HRS should be managed as
inpatients for diagnostic investigation and treatment. Vital
signs, urine output, and blood chemistry should be closely
monitored. Because most patients have dilutional
hyponatraemia (serum sodium below 130 mmol/L), total
fluid intake (both oral and intravenous fluids) should be
restricted to avoid a positive fluid balance, which would
lead to a further reduction in serum sodium
concentration. In most cases, total fluid intake should be
kept around 1000 mL daily. In patients with severe
oligoanuria, more severe fluid restriction (500–1000 mL
daily) may be needed to prevent a positive fluid balance
and a progressive decline in serum sodium concentration.
However, such a low input can be difficult to achieve
because the administration of fluids cannot be reduced to
such an extent in some patients and restriction is poorly
tolerated by conscious patients. The administration of
saline solutions can increase ascites and oedema greatly
because of the presence of severe renal sodium retention
and therefore is not recommended. For this reason and
the absence of severe metabolic acidosis in most patients,
the routine administration of sodium bicarbonate is also
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SEMINAR
not advisable. Potassium-sparing diuretics should be
withheld because of the risk of inducing severe
hyperkalaemia. Early identification of infections and
treatment with broad-spectrum antibiotics is
fundamental, since severe infections are common and
contribute to death in these patients. The efficacy of
antibiotic prophylaxis for the prevention of infections in
patients with HRS has not been assessed.
Several therapeutic approaches can be used in the
management of type 1 HRS (panel 1).
Liver transplantation
The treatment of choice for patients with cirrhosis and
type 1 HRS who are suitable for the procedure is liver
transplantation, because it allows both the liver disease
and the associated renal failure to be cured.55–58 The most
common contraindications for transplantation in HRS are
advanced age, active alcoholism, and infection. The main
problem in the use of liver transplantation for type 1 HRS
is that many patients die before transplantation is possible
because of the short survival expectancy and long waiting
times in most transplant centres. The issue can be solved
by assigning these patients a high priority for
transplantation from a cadaveric donor. This approach
was used with the former method of organ allocation used
by the United Network for Organ Sharing in the USA,
which classified patients with HRS in the 2a status, with a
median waiting time of about 7 days.59 Now this system
has been changed and livers are allocated on the basis of
the MELD (model of end-stage liver disease) score, which
is obtained by a formula including serum bilirubin, serum
creatinine, and international normalised ratio.60–62 Patients
with HRS have high MELD scores even when liver
function is preserved. This system was implemented in
the USA in early 2002, and the initial results of its use
have been reported recently.63 The policies for allocation
of livers from cadaveric donors are not uniform in other
countries. Whatever the system used for organ allocation,
HRS should probably be treated before transplantation is
done in an attempt to improve renal function. This step
may help reduce the (moderately) higher morbidity and
mortality after transplantation reported in patients with
HRS than in those without HRS.64–66 In fact, the outcome
of transplantation for patients with HRS treated with
vasoconstrictors (vasopressin analogues) before the
procedure does not differ from that of patients without
HRS.67 Combined liver and kidney transplantation for
patients with HRS does not improve the overall results
obtained with liver transplantation alone and should not
be used.68
Another theoretical option for transplantation of
patients with HRS is transplantation of the right hepatic
Panel 1: Recommendations for the management of
type 1 HRS
Consider the patient for liver transplantation.
Set up high priority for transplantation in suitable patients.
Start vasoconstrictors plus intravenous albumin.
Consider TIPS in patients without severe liver failure in whom
vasoconstrictors have failed.
Consider renal replacement therapy if there is pulmonary
oedema, severe hypokalaemia, or metabolic acidosis not
responding to medical therapy.
If high priority for cadaveric liver transplantation is not
possible, consider liver transplantation from a living relative
in patients with moderate liver failure in whom renal function
has improved after therapy.
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lobe from a living donor.69 However, this is not the option
of choice because few patients have suitable living donors
and the assessment of the donor requires extensive
investigation, which in some cases may take too long.
Moreover, this procedure carries a significant risk for the
healthy donor, and the results obtained in patients with
severely decompensated liver disease are probably not as
good as those obtained with cadaveric liver
transplantation.70 Therefore, type 1 HRS is probably not
an indication for living-related liver transplantation at
least at present. Nevertheless, this procedure may be
considered for selected patients with preserved liver
function in whom renal function has improved after
therapy in settings or countries where livers are not
prioritised according to disease severity.
Vasoconstrictors
The only effective medical therapy currently available for
the management of HRS is administration of
vasoconstrictors. The rationale behind this approach is to
improve circulatory function by causing vasoconstriction
of the extremely dilated splanchnic arterial bed, which
subsequently suppresses the activity of the endogenous
vasoconstrictor systems and results in an increase in renal
perfusion (figure 1).71 Two types of drugs have been used
so far: vasopressin analogues (ornipressin and terlipressin)
and ␣-adrenergic agonists (norepinephrine and
midodrine), which act on V1 vasopressin receptors and
␣1-adrenergic receptors, respectively, present in vascular
smooth-muscle cells. In most studies, both types of drug11
have been given in combination with intravenous albumin
to improve further the arterial underfilling (table). The
use of albumin appears to increase the efficacy of
vasoconstrictor drugs.35 Ornipressin is effective but its use
is not recommended because of the development of severe
ischaemic complications in up to a third of patients.32,72
Terlipressin is the vasoconstrictor that has been used most
frequently in HRS.34,35,73–76 Administration of this drug
(0·5–2·0 mg over 4–6 h intravenously) is associated with a
complete renal response (reduction of serum creatinine
below 133 ␮mol/L) in 50–75% of patients, according to
various studies. Predictors of lack of response to
terlipressin include old age, severe liver failure (Child-
Pugh score greater than 13), and omission of concomitant
albumin administration.34,35 The improvement in GFR
occurs slowly over several days and is associated in some,
but not all, cases with an increase in excretion of sodium
and free water and improvement in serum sodium
concentration. Despite the improvement in GFR and the
decrease in serum creatinine to normal or near-normal
concentrations, GFR remains below normal values in
most responding patients.35,74 Recurrence of HRS after
treatment withdrawal in responders is uncommon (about
15% of patients) and retreatment is effective in most
cases. The frequency of ischaemic side-effects requiring
Drug and Dose range Maximum duration Potential
references of therapy (days) side-effects
Terlipressin34,35,73–76 0·5–2·0 mg 15 Peripheral,
every 4 h as splanchnic, or
intravenous cardiac
bolus ischaemia
Norepinephrine78 0·5–3·0 mg/h 15 Peripheral,
intravenous splanchnic, or
infusion cardiac
ischaemia
Midodrine77 7·5–12·5 mg Indefinite? Not reported
every 8 h by
mouth
Drugs used in the therapy of hepatorenal syndrome
1824
For personal use. Only reproduce with permission from The Lancet publishing Group.
the discontinuation of terlipressin treatment (5–10%) is
lower than that with ornipressin (30–50%). Responders to
terlipressin have better survival than non-responders,
which suggests an effect of the drug on survival.34,35 There
are two major shortcomings of treatment with terlipressin:
the drug is not available in some countries and its cost is
high, which limits its use in some parts of the world.
␣-adrenergic agonists (norepinephrine, midodrine) are an
attractive alternative to terlipressin because they are
cheaper, widely available, and apparently as effective as
terlipressin.77,78 However, information on the efficacy and
side-effects of ␣-adrenergic agonists in patients with type
1 HRS is still very limited. Octreotide, which causes
splanchnic vasoconstriction probably mediated by
inhibition of some vasodilator peptides of splanchnic
origin and not through a direct effect on vascular smooth-
muscle cells, is not effective in the management of HRS.79
Transjugular intrahepatic portosystemic shunts
Only a few studies have reported on the effects of
transjugular intrahepatic portosystemic shunts (TIPS) in
patients with type 1 HRS.80,81 This procedure consists of
insertion of an intrahepatic stent between the portal and
hepatic veins by a transjugular approach. The main effect
is to lower portal pressure.82 In type 1 HRS, TIPS improve
circulatory function and reduce the activity of
vasoconstrictor systems.80,81 These effects are associated
with a slow, moderate to strong increase in renal perfusion
and GFR and a fall in serum creatinine concentrations in
about 60% of patients. Median survival after TIPS in
type 1 HRS is between 2 months and 4 months.80,81 As
with vasoconstrictor drugs, the improved renal function
probably, but not definitely, results in longer survival.81
Information currently available on the use of TIPS in type
1 HRS has been obtained in a very selected population of
patients and may not be applicable to the whole
population of such patients. In fact, TIPS are thought to
be contraindicated in patients with severe liver failure
(high serum bilirubin concentrations and/or Child-Pugh
score greater than 12) or severe hepatic encephalopathy
because of the risk of inducing irreversible liver failure or
chronic disabling hepatic encephalopathy.82,83 No studies
have been reported that compared TIPS and
vasoconstrictors in type 1 HRS. Until comparative studies
are undertaken, vasoconstrictors appear to be the
treatment of choice in type 1 HRS because of apparently
similar efficacy, wider availability, and lower costs than
TIPS.
Other therapeutic methods
Renal replacement therapy (haemodialysis) is frequently
used in the management of patients with type 1 HRS,
especially those who are candidates for liver
transplantation, in an attempt to keep them alive until the
transplantation can be done or a spontaneous
improvement in renal function occurs.57,84 However, the
potential benefit of this approach has not been
unequivocally established. Clinical experience is that most
patients do not tolerate haemodialysis and develop
important side-effects, including severe arterial
hypotension, bleeding, and infections that can lead to
death during treatment. Moreover, findings that indicate
the need for renal replacement therapy (severe fluid
overload, acidosis, or hyperkalaemia) are uncommon, at
least in early stages of type 1 HRS. Therefore, the initial
therapy for these patients should probably include
measures aimed at improving circulatory function
(vasoconstrictors, TIPS) and not haemodialysis. Other
techniques such as continuous arteriovenous or
THE LANCET • Vol 362 • November 29, 2003 • www.thelancet.com

venovenous haemofiltration or haemodiafiltration have
been used in isolated cases.84 These techniques may be
helpful in selected patients with severe anasarca because
they may help achieve negative fluid balance without
causing hypotension. However, the available evidence is
insufficient and the role of these techniques in the
management of patients with HRS remains undefined.
Extracorporeal albumin dialysis, a system that uses an
albumin-containing dialysate that is recirculated and
perfused through charcoal and anion-exchanger columns,
has been reported to improve renal function and survival
in a small series of patients with HRS, but these results
require confirmation in larger series of patients.85 The
efficacy of drugs with renal vasodilator activity, such as
dopamine or prostaglandins, has not been proven and
they are therefore not recommended.57 N-acetylcysteine
has shown some efficacy in a small series of patients but
these results need confirmation.86
Management of type 2 HRS
Unlike patients with type 1 HRS, those with type 2 HRS
can be managed as outpatients unless they develop
complications of cirrhosis that necessitate hospital
admission. The commonest clinical finding in these
patients is refractory ascites. Diuretics should be given only
if they cause a significant natriuresis (ie, urine sodium
excretion of more than 30 mmoles daily). Care should be
taken with the use of spironolactone in these patients
because of the risk of hyperkalaemia. Dietary sodium
restriction (40–80 mmoles per day) is important to
decrease the ascites formation rate, since sodium excretion
is severely impaired and most patients respond poorly or
not at all to diuretics. Repeated paracentesis with
intravenous albumin is probably the method of choice for
the treatment of episodes of large ascites in these patients.87
If dilutional hyponatraemia is present, total fluid intake
should be restricted to about 1000 mL/day. Bacterial
infections should be diagnosed and treated early to avoid
the risk of precipitating type 1 HRS. The usefulness of
prophylactic antibiotics has not been assessed and would
be worthy of study. Recommendations for the management
of patients with type 2 HRS are outlined in panel 2.
Liver transplantation
Liver transplantation is the treatment of choice for
suitable patients. The short survival of patients with type 2
HRS (median 6 months) should be taken into account
when these patients are assessed for liver transplantation.
Treatment of HRS before transplantation with some of
the procedures discussed below may be beneficial to
improve the short-term and long-term outcome after
transplantation.67
Vasoconstrictors
There is limited information on the use of
vasoconstrictors in the treatment of patients with type 2
Panel 2: Recommendations for management of
type 2 HRS
Consider the patient for liver transplantation.
Use diuretics for management of ascites only if they cause
significant natriuresis (>30 mmoles per day). Restrict dietary
sodium intake to 40–80 mmoles per day.
Use repeated paracentesis plus intravenous albumin to treat
recurrent large/tense ascites.
Restrict fluid intake if hyponatraemia is present.
Consider vasoconstrictors or TIPS before liver transplantation.
THE LANCET • Vol 362 • November 29, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet publishing Group.
SEMINAR
HRS, but some reports suggest that, as in type 1, the
administration of vasoconstrictors improves renal function
in these patients.35,88 However, more information is
required before a definitive conclusion about this
therapeutic approach can be taken.
Transjugular intrahepatic portosystemic shunts
The use of TIPS in patients with type 2 HRS is associated
with an improvement of renal function, better control of
ascites, and reduced risk of progression to type 1
HRS.81,87,89–92 However, a subanalysis of patients with type
2 HRS included in a randomised study comparing TIPS
and repeated paracentesis plus intravenous albumin in
patients with cirrhosis and refractory ascites showed that
the use of TIPS was not associated with improved survival
compared with the other two treatments.87 Therefore, the
beneficial effects of TIPS in reducing the rates of ascites
recurrence and progression to type 1 HRS should weighed
against the lack of improvement in survival, increased risk
of encephalopathy, and high costs.
Prevention
Until very recently, no effective methods for prevention of
HRS existed. However, two recent studies have shown
that the syndrome can be prevented effectively in two
specific clinical settings: spontaneous bacterial peritonitis
and alcoholic hepatitis. In spontaneous bacterial
peritonitis, the intravenous administration of albumin
(1·5 g/kg at the diagnosis of the infection and 1 g/kg 48 h
later) together with antibiotics greatly decreases the risk of
HRS compared with the standard treatment of antibiotics
alone (10% in the albumin group vs 33% in the non-
albumin group).38 Moreover, hospital mortality is also
lower in patients receiving albumin (10% vs 29%). The
beneficial effect of albumin is probably related to its
capacity to prevent arterial underfilling and subsequent
activation of vasoconstrictor systems during the infection.
In patients with alcoholic hepatitis, the administration of
pentoxifylline (400 mg three times daily) decreases the
rate of occurrence of HRS and mortality (8% and 24%,
respectively) compared with a control group (35% and
46%, respectively).9 The beneficial effect of pentoxifylline
is probably related to its capacity to inhibit production of
tumour necrosis factor, but other mechanisms such as
inhibition of vascular endothelial growth factor and tissue
factor may also have a role.93 Although the beneficial
effects obtained in these two clinical trials need to be
confirmed in other studies, the treatments represent the
first big step towards effective prevention of HRS in
patients with end-stage liver disease. Furthermore, the
relation between prevention of HRS and improved
survival in the two settings strongly supports the concept
that the presence of renal failure adversely affects the
survival of patients with end-stage liver disease.
Conflict of interest statement
Pere Ginès has participated in scientific symposia sponsored by Grífols
International (Barcelona, Spain) and Laboratoire Français du
Fractionnement et des Biotechnologies (LBF, Paris, France); both
companies manufacture human albumin. Vicente Arroyo has participated
in scientific symposia sponsored by Grífols International and is a member
of a steering committee of Teraklin AG (Rostock, Germany), the
manufacturer of the molecular adsorbents recirculating system (MARS)
device. Juan Rodés and Mónica Guevara have no conflicts of interest. No
financial support has been received from the companies producing drugs
or medical devices described in this seminar.
Acknowledgments
We thank Blas Calahorra, Andrés Cárdenas, Dara de las Heras,
Wladimiro Jiménez, Rolando Ortega, Ramón Planas, and Juan Uriz for
their work in some of the studies reported in this seminar.
1825
SEMINAR
There was no funding source, other than The Lancet for the preparation,
analysis, or writing of this seminar. Some of the recent clinical studies
reported here and carried out in our unit have been supported by grants
from Marato Fundació TV3 (U-2000-TV2710), Fondo de
Investigaciones Sanitarias de la Seguridad Social (FISS 00/0618 and
02/0701), Dirección General de Investigación Científico y Técnica (SAF
2001/0300), Instituto Reina Sofía de Investigación Nefrológica, and
Instituto de Salud Carlos III (C03/2).
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